Over the past year the Medical Breast Cancer Section has continued research into four main areas in breast cancer clinical treatment: 1) Dose Intensive Induction Chemotherapy; 2) New Drug Development; 3) Targeted Therapies; and 4) Breast Cancer Chemoprevention and Identification of Surrogate Biomarkers of Breast Cancer Progression. We have completed our dose intensity clinical trial of FLAC chemotherapy plus 1L-3 and GM-CSF for patients with newly diagnosed advanced breast cancer. In addition, we have analyzed the results from the five patients treated with high dose ICE chemotherapy and autologous stem cells that have been marked with the neomycin resistance gene. The study of MDR-1 transduction of hematopoietic stem cells will begin August, 1994. We completed the Phase I study of taxol and high dose cyclophosphamide with G-CSF in patients with metastatic breast cancer and have found it to be an active regimen in previously treated patients. This study has emphasized breast cancer tissue acquisition for immunohistochemical analysis of Pgp expression and these analyses are ongoing. Our taxol plus R-verapamil Phase I study yielded interesting results regarding Pgp expression in pretreated metastatic breast cancer and pharmacokinetics. Another new drug under study is topotecan, a promising new topoisomerase I inhibitor which we are combining with doxorubicin in an ongoing Phase I study with particular attention to bone marrow synchronization. We will reopen our Phase I study of a targeted therapy, the murine monoclonal antibody CC-49 labeled with the new beta emitter, Lutetium-177 with a newly formulated version of the conjugate aimed at reducing RES uptake. This study represents the first human trial of this novel radioisotope. Another Phase II trial combining tamoxifen with the synthetic retinoid, 4-HPR, is currently ongoing with a major emphasis on studying the upregulation of TGF-beta expression in tumor and normal tissue. Our primary new initiative over the past year has been to develop strategies to develop intermediate molecular biomarkers for breast cancer prevention studying the contralateral breasts of breast cancer patients as well as preinvasive proliferative lesions in high risk patients. Our pilot study of tamoxifen and 4-HPR in women at high risk of developing breast cancer has just opened with a major emphasis on defining intermediate surrogate biomarkers of malignant progression. We are also working with NCHGR to define appropriate chemopreventative strategies for women who carry the BRCA-l gene.